supplementary materials


nc2311 scheme

Acta Cryst. (2013). E69, o935    [ doi:10.1107/S1600536813013512 ]

tert-Butyl N-[(3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl]-N-methylcarbamate

M. Gehringer, M. Forster, D. Schollmeyer and S. Laufer

Abstract top

The piperidine ring of the title compound, C15H25N3O3, adopts a slightly distorted chair conformation with the cis substituents displaying an N-C-C-C torsion angle of 43.0 (3)°. The cyano group (plane defined by C-C-C[triple bond]N atoms) is bent slightly out of the plane of the amide group by 13.3 (2)°. The carbamate group is oriented at a dihedral angle of 60.3 (5)° relative to the amide group.

Comment top

Tofacitinib (CP690,550) is a potent and selective Janus Kinase (JAK) 1/3 inhibitor (Changelian et al. (2003) and Flanagan et al., (2010)) which has recently been approved by the US Food and Drug Administration for the treament of rheumatoid athritis. Furthermore, it is currently in late stage clinical trials for treatment of psoriasis, inflammatory bowel disease, transplant rejection and other immunological disorders (Zerbini & Lomonte, (2012)). Searching for novel JAK inhibitors, the title compound was synthesized as a key intermediate possessing the Boc-protected Tofacitinib side chain.

In the crystal structure of the title compound the piperidine ring adopts a slightly distorted chair conformation with a torsion angle between the cis substituents of 43.0 (3)°. The carbamate group shows a dihedral angle of 60.3 (5)° relative to the amide group. The plane defined by atoms C17, C19, C20 and N21 is slightly bent out of the plane of the amide group by 13.3 (2)°.

Related literature top

For the biological activity and structure–activity relationships of Tofacitinib {systematic name: 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile} derivatives, see: Changelian et al. (2003); Flanagan et al. (2010); Zerbini & Lomonte (2012). For details of the synthesis, see: Babu et al. (2010).

Experimental top

The title compound was prepared by cyanoacetylation of a precursor possessing a free piperidine NH-function (Babu et al., (2010)) using dicyclohexylcarbodiimide (DCC) and cyanoacetic acid.

tert-Butyl-N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]carbamate (2.80 g, 12.3 mmol) was dissolved in 25 ml of dry methylen chloride and stirred under argon atmosphere. Cyano acetic acid (0.82 g, 9.64 mmol) and N,N'-dicyclohexylcarbodiimide (1.99 g, 9.64 mmol) was added in one portion while cooling with ice. After 15 min at 273 K, the ice bath was removed, the mixture warmed to room temperature (298 K) and stirring was continued for 3 h. N,N'-dicyclohexylurea was removed by filtration, washed with methylen chloride and the filtrate concentrated under reduced pressure. Purification by column chromatography (SiO2, methylen chloride/ethyl acetate: 7 + 3) yielded the title compound as colorless solid (2.18 g, 84.3%). Crystals of the title compound were obtained by slow evaporation of methanol at room temperature (298 K).

Refinement top

Hydrogen atoms attached to carbons were placed at calculated positions with C—H = 0.95 Å (aromatic) or 0.99–1.00 Å (sp3 C-atom). All H atoms were refined with isotropic displacement parameters (set at 1.2–1.5 times of the Ueq of the parent atom). Because no strong anomalous scattering atoms are present Friedel opposites were merged in the refinement. The absolute configuration was assigned according to the synthesis.

Computing details top

Data collection: APEX2 (Bruker, 2006); cell refinement: SAINT (Bruker, 2006); data reduction: SAINT (Bruker, 2006); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: PLATON (Spek, 2009).

Figures top
[Figure 1] Fig. 1. Crystal structure (oder molecular structure) of the title compound with labeling and displacement ellipsoids drawn at the 50% probability level.
tert-Butyl N-[(3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl]-N-methylcarbamate top
Crystal data top
C15H25N3O3F(000) = 320
Mr = 295.38Dx = 1.190 Mg m3
Monoclinic, P21Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ybCell parameters from 1671 reflections
a = 7.1786 (11) Åθ = 2.6–27.7°
b = 7.3213 (10) ŵ = 0.08 mm1
c = 16.042 (2) ÅT = 173 K
β = 102.196 (4)°Block, colourless
V = 824.1 (2) Å30.60 × 0.35 × 0.10 mm
Z = 2
Data collection top
Bruker SMART APEXII
diffractometer
1818 reflections with I > 2σ(I)
Radiation source: sealed TubeRint = 0.031
Graphite monochromatorθmax = 27.8°, θmin = 2.6°
CCD scanh = 89
5061 measured reflectionsk = 99
2115 independent reflectionsl = 1921
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.038Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.101H-atom parameters constrained
S = 1.03 w = 1/[σ2(Fo2) + (0.0542P)2 + 0.0849P]
where P = (Fo2 + 2Fc2)/3
2115 reflections(Δ/σ)max = 0.001
195 parametersΔρmax = 0.24 e Å3
1 restraintΔρmin = 0.17 e Å3
Crystal data top
C15H25N3O3V = 824.1 (2) Å3
Mr = 295.38Z = 2
Monoclinic, P21Mo Kα radiation
a = 7.1786 (11) ŵ = 0.08 mm1
b = 7.3213 (10) ÅT = 173 K
c = 16.042 (2) Å0.60 × 0.35 × 0.10 mm
β = 102.196 (4)°
Data collection top
Bruker SMART APEXII
diffractometer
1818 reflections with I > 2σ(I)
5061 measured reflectionsRint = 0.031
2115 independent reflectionsθmax = 27.8°
Refinement top
R[F2 > 2σ(F2)] = 0.038H-atom parameters constrained
wR(F2) = 0.101Δρmax = 0.24 e Å3
S = 1.03Δρmin = 0.17 e Å3
2115 reflectionsAbsolute structure: ?
195 parametersFlack parameter: ?
1 restraintRogers parameter: ?
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.4456 (3)0.3404 (3)0.18701 (13)0.0302 (4)
H10.47160.21100.17310.036*
C20.6397 (3)0.4395 (4)0.20174 (18)0.0405 (6)
H20.70500.39450.15640.049*
C30.6252 (3)0.6475 (3)0.19155 (17)0.0399 (6)
H3A0.58130.70080.24080.048*
H3B0.75280.69830.19110.048*
C40.4877 (3)0.7001 (3)0.10969 (16)0.0395 (5)
H4A0.47370.83460.10660.047*
H4B0.53870.65920.06010.047*
N50.3008 (3)0.6153 (3)0.10671 (12)0.0312 (4)
C60.3066 (3)0.4151 (3)0.10847 (14)0.0330 (5)
H6A0.34490.37020.05630.040*
H6B0.17720.36770.10810.040*
N70.3602 (2)0.3322 (2)0.26269 (11)0.0285 (4)
C80.2959 (4)0.4987 (3)0.29674 (17)0.0402 (6)
H8A0.39260.59410.29890.060*
H8B0.27570.47570.35440.060*
H8C0.17600.53880.25990.060*
C90.3408 (3)0.1672 (3)0.29731 (13)0.0290 (4)
O100.3892 (2)0.0216 (2)0.27102 (10)0.0394 (4)
O110.2571 (2)0.1828 (2)0.36532 (10)0.0372 (4)
C120.2052 (3)0.0207 (3)0.40890 (14)0.0375 (5)
C130.3833 (4)0.0846 (4)0.45076 (17)0.0512 (7)
H13A0.44340.13620.40660.077*
H13B0.34820.18360.48560.077*
H13C0.47280.00190.48700.077*
C140.0646 (4)0.0948 (4)0.34738 (17)0.0433 (6)
H14A0.12610.14240.30280.065*
H14B0.04550.02000.32120.065*
H14C0.02210.19700.37820.065*
C150.1100 (5)0.1057 (4)0.47614 (17)0.0496 (7)
H15A0.20070.18640.51300.074*
H15B0.06970.00880.51060.074*
H15C0.00140.17650.44800.074*
C160.7654 (4)0.3823 (5)0.2870 (2)0.0702 (10)
H16A0.89330.43370.29190.105*
H16B0.77360.24870.28980.105*
H16C0.70990.42770.33380.105*
C170.1318 (3)0.7016 (3)0.09444 (12)0.0283 (4)
O180.0215 (2)0.6227 (2)0.08811 (11)0.0374 (4)
C190.1360 (3)0.9103 (3)0.09008 (14)0.0340 (5)
H19A0.23740.95730.13690.041*
H19B0.16690.94820.03530.041*
C200.0465 (4)0.9893 (3)0.09718 (15)0.0372 (5)
N210.1875 (3)1.0566 (3)0.10290 (15)0.0513 (6)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0333 (10)0.0234 (10)0.0361 (11)0.0038 (9)0.0125 (8)0.0038 (9)
C20.0278 (11)0.0393 (14)0.0574 (15)0.0051 (10)0.0160 (10)0.0009 (12)
C30.0269 (10)0.0385 (14)0.0575 (15)0.0046 (10)0.0159 (10)0.0048 (11)
C40.0391 (11)0.0325 (12)0.0511 (14)0.0060 (10)0.0187 (10)0.0034 (11)
N50.0344 (9)0.0239 (9)0.0359 (10)0.0030 (8)0.0091 (7)0.0008 (8)
C60.0429 (12)0.0234 (10)0.0331 (11)0.0014 (9)0.0090 (9)0.0037 (9)
N70.0327 (8)0.0233 (9)0.0310 (9)0.0052 (8)0.0099 (7)0.0018 (8)
C80.0558 (14)0.0215 (11)0.0508 (14)0.0034 (10)0.0282 (11)0.0025 (10)
C90.0314 (9)0.0258 (10)0.0289 (10)0.0031 (9)0.0038 (8)0.0018 (9)
O100.0546 (10)0.0241 (8)0.0414 (9)0.0088 (8)0.0147 (7)0.0021 (7)
O110.0570 (9)0.0218 (7)0.0366 (8)0.0036 (8)0.0187 (7)0.0002 (7)
C120.0557 (13)0.0239 (11)0.0341 (12)0.0063 (11)0.0124 (10)0.0032 (10)
C130.0667 (17)0.0402 (13)0.0417 (14)0.0094 (13)0.0000 (12)0.0058 (12)
C140.0537 (14)0.0294 (11)0.0482 (14)0.0010 (11)0.0138 (11)0.0000 (11)
C150.0788 (18)0.0346 (12)0.0431 (14)0.0021 (13)0.0300 (13)0.0024 (11)
C160.0317 (12)0.070 (2)0.099 (3)0.0032 (14)0.0084 (14)0.015 (2)
C170.0360 (10)0.0258 (10)0.0230 (10)0.0026 (9)0.0059 (8)0.0023 (8)
O180.0355 (8)0.0322 (8)0.0445 (9)0.0042 (7)0.0085 (7)0.0065 (7)
C190.0398 (12)0.0286 (11)0.0321 (11)0.0018 (10)0.0044 (9)0.0035 (9)
C200.0506 (14)0.0270 (11)0.0325 (11)0.0005 (11)0.0058 (10)0.0004 (9)
N210.0589 (13)0.0413 (13)0.0545 (13)0.0095 (12)0.0139 (11)0.0015 (11)
Geometric parameters (Å, º) top
C1—N71.472 (3)C9—O111.357 (3)
C1—C61.533 (3)O11—C121.465 (3)
C1—C21.544 (3)C12—C141.512 (4)
C1—H11.0000C12—C131.522 (3)
C2—C161.529 (4)C12—C151.526 (3)
C2—C31.533 (4)C13—H13A0.9800
C2—H21.0000C13—H13B0.9800
C3—C41.516 (4)C13—H13C0.9800
C3—H3A0.9900C14—H14A0.9800
C3—H3B0.9900C14—H14B0.9800
C4—N51.470 (3)C14—H14C0.9800
C4—H4A0.9900C15—H15A0.9800
C4—H4B0.9900C15—H15B0.9800
N5—C171.345 (3)C15—H15C0.9800
N5—C61.467 (3)C16—H16A0.9800
C6—H6A0.9900C16—H16B0.9800
C6—H6B0.9900C16—H16C0.9800
N7—C91.349 (3)C17—O181.228 (3)
N7—C81.451 (3)C17—C191.530 (3)
C8—H8A0.9800C19—C201.459 (3)
C8—H8B0.9800C19—H19A0.9900
C8—H8C0.9800C19—H19B0.9900
C9—O101.223 (3)C20—N211.147 (3)
N7—C1—C6112.35 (17)O10—C9—O11123.9 (2)
N7—C1—C2114.38 (18)N7—C9—O11110.90 (18)
C6—C1—C2111.59 (19)C9—O11—C12121.04 (17)
N7—C1—H1105.9O11—C12—C14110.10 (18)
C6—C1—H1105.9O11—C12—C13110.3 (2)
C2—C1—H1105.9C14—C12—C13112.8 (2)
C16—C2—C3112.4 (2)O11—C12—C15101.76 (19)
C16—C2—C1110.6 (2)C14—C12—C15110.7 (2)
C3—C2—C1114.31 (19)C13—C12—C15110.8 (2)
C16—C2—H2106.3C12—C13—H13A109.5
C3—C2—H2106.3C12—C13—H13B109.5
C1—C2—H2106.3H13A—C13—H13B109.5
C4—C3—C2111.2 (2)C12—C13—H13C109.5
C4—C3—H3A109.4H13A—C13—H13C109.5
C2—C3—H3A109.4H13B—C13—H13C109.5
C4—C3—H3B109.4C12—C14—H14A109.5
C2—C3—H3B109.4C12—C14—H14B109.5
H3A—C3—H3B108.0H14A—C14—H14B109.5
N5—C4—C3110.11 (18)C12—C14—H14C109.5
N5—C4—H4A109.6H14A—C14—H14C109.5
C3—C4—H4A109.6H14B—C14—H14C109.5
N5—C4—H4B109.6C12—C15—H15A109.5
C3—C4—H4B109.6C12—C15—H15B109.5
H4A—C4—H4B108.2H15A—C15—H15B109.5
C17—N5—C6119.57 (19)C12—C15—H15C109.5
C17—N5—C4126.53 (19)H15A—C15—H15C109.5
C6—N5—C4113.55 (19)H15B—C15—H15C109.5
N5—C6—C1112.52 (19)C2—C16—H16A109.5
N5—C6—H6A109.1C2—C16—H16B109.5
C1—C6—H6A109.1H16A—C16—H16B109.5
N5—C6—H6B109.1C2—C16—H16C109.5
C1—C6—H6B109.1H16A—C16—H16C109.5
H6A—C6—H6B107.8H16B—C16—H16C109.5
C9—N7—C8121.94 (17)O18—C17—N5123.7 (2)
C9—N7—C1118.25 (17)O18—C17—C19119.5 (2)
C8—N7—C1119.80 (18)N5—C17—C19116.7 (2)
N7—C8—H8A109.5C20—C19—C17111.4 (2)
N7—C8—H8B109.5C20—C19—H19A109.3
H8A—C8—H8B109.5C17—C19—H19A109.3
N7—C8—H8C109.5C20—C19—H19B109.3
H8A—C8—H8C109.5C17—C19—H19B109.3
H8B—C8—H8C109.5H19A—C19—H19B108.0
O10—C9—N7125.24 (18)N21—C20—C19177.9 (3)
N7—C1—C2—C1643.0 (3)C2—C1—N7—C867.0 (3)
C6—C1—C2—C16171.9 (2)C8—N7—C9—O10178.8 (2)
N7—C1—C2—C385.0 (3)C1—N7—C9—O100.2 (3)
C6—C1—C2—C343.9 (3)C8—N7—C9—O110.3 (3)
C16—C2—C3—C4175.6 (2)C1—N7—C9—O11178.92 (17)
C1—C2—C3—C448.5 (3)O10—C9—O11—C124.7 (3)
C2—C3—C4—N555.2 (3)N7—C9—O11—C12174.44 (18)
C3—C4—N5—C17126.0 (2)C9—O11—C12—C1460.1 (3)
C3—C4—N5—C660.9 (3)C9—O11—C12—C1365.0 (3)
C17—N5—C6—C1129.3 (2)C9—O11—C12—C15177.46 (19)
C4—N5—C6—C157.1 (3)C6—N5—C17—O183.4 (3)
N7—C1—C6—N583.0 (2)C4—N5—C17—O18176.1 (2)
C2—C1—C6—N547.0 (3)C6—N5—C17—C19177.8 (2)
C6—C1—N7—C9117.2 (2)C4—N5—C17—C195.1 (3)
C2—C1—N7—C9114.3 (2)O18—C17—C19—C2012.5 (3)
C6—C1—N7—C861.5 (3)N5—C17—C19—C20166.36 (18)
Acknowledgements top

The authors thank Ellen Pfaffenrot and Peter Keck for fruitful discussions and suggestions.

references
References top

Altomare, A., Burla, M. C., Camalli, M., Cascarano, G. L., Giacovazzo, C., Guagliardi, A., Moliterni, A. G. G., Polidori, G. & Spagna, R. (1999). J. Appl. Cryst. 32, 115–119.

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Bruker (2006). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.

Changelian, P. S., et al. (2003). Science, 302, 875–878.

Flanagan, M. E., et al. (2010). J. Med. Chem. 53, 8468–8484.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.

Spek, A. L. (2009). Acta Cryst. D65, 148–155.

Zerbini, C. A. & Lomonte, A. B. (2012). Expert Rev. Clin. Immunol. 8, 319–331.